The NADPH oxidase inhibitor diphenyleneiodonium suppresses Ca signaling and contraction in rat cardiac myocytes.

Diphenyleneiodonium (DPI) has been widely used as an inhibitor of NADPH oxidase (Nox) to discover its function in cardiac myocytes under various stimuli. However, the effects of DPI itself on Ca signaling and contraction in cardiac myocytes under control conditions have not been understood. We investigated the effects of DPI on contraction and Ca signaling and their underlying mechanisms using video edge detection, confocal imaging, and whole-cell patch clamp technique in isolated rat cardiac myocytes.

Modeling acute myocardial infarction and cardiac fibrosis using human induced pluripotent stem cell-derived multi-cellular heart organoids.

Heart disease involves irreversible myocardial injury that leads to high morbidity and mortality rates. Numerous cell-based cardiac in vitro models have been proposed as complementary approaches to non-clinical animal research. However, most of these approaches struggle to accurately replicate adult human heart conditions, such as myocardial infarction and ventricular remodeling pathology.

Accelerated Discovery of Novel Garnet-Type Solid-State Electrolyte Candidates via Machine Learning.

All-solid-state batteries (ASSBs) have attracted considerable attention because of their higher energy density and stability than conventional lithium-ion batteries (LIBs). For the development of promising ASSBs, solid-state electrolytes (SSEs) are essential to achieve structural integrity. Thus, in this study, a machine-learning-based surrogate model was developed to search for ideal garnet-type SSE candidates.

Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts.

Background: Exercise training, and catecholaminergic stimulation, increase the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy correlated with plakophilin-2 (PKP2) mutations. Separate data show that reduced abundance of PKP2 leads to dysregulation of intracellular Ca (Ca) homeostasis. Here, we study the relation between excercise, catecholaminergic stimulation, Ca homeostasis, and arrhythmogenesis in PKP2-deficient murine hearts.

Prediction of dielectric constants of ABO-type perovskites using machine learning and first-principles calculations.

In this study, the machine-learning method, combined with density functional perturbation theory (DFPT) calculations, was implemented to predict and validate the dielectric constants of ABO-type perovskites. For the construction of the training database, the dielectric constants of 7113 inorganic materials were extracted from the Materials Project. The chemical, structural, and physical descriptors were generated and trained using the gradient-boosting-based regressor after feature engineering.

Truncated Milk Fat Globule-EGF-like Factor 8 Ameliorates Liver Fibrosis via Inhibition of Integrin-TGFβ Receptor Interaction.

Milk fat globule-EGF factor 8 (MFG-E8) protein is known as an immunomodulator in various diseases, and we previously demonstrated the anti-fibrotic role of MFG-E8 in liver disease. Here, we present a truncated form of MFG-E8 that provides an advanced therapeutic benefit in treating liver fibrosis. The enhanced therapeutic potential of the modified MFG-E8 was demonstrated in various liver fibrosis animal models, and the efficacy was further confirmed in human hepatic stellate cells and a liver spheroid model.

Regulation of Survival Motor Neuron Gene Expression by Calcium Signaling.

Spinal muscular atrophy (SMA) is caused by homozygous () gene deletion, leaving a duplicate gene, , as the sole source of SMN protein. However, a defect in SMN2 splicing, involving exon 7 skipping, results in a low level of functional SMN protein. Therefore, the upregulation of SMN protein expression from the gene is generally considered to be one of the best therapeutic strategies to treat SMA.

Modulations of Cardiac Functions and Pathogenesis by Reactive Oxygen Species and Natural Antioxidants.

Homeostasis in the level of reactive oxygen species (ROS) in cardiac myocytes plays a critical role in regulating their physiological functions. Disturbance of balance between generation and removal of ROS is a major cause of cardiac myocyte remodeling, dysfunction, and failure. Cardiac myocytes possess several ROS-producing pathways, such as mitochondrial electron transport chain, NADPH oxidases, and nitric oxide synthases, and have endogenous antioxidation mechanisms.

Structural and Functional Characterization of a Na1.5-Mitochondrial Couplon.

Rationale: The cardiac sodium channel Na1.5 has a fundamental role in excitability and conduction. Previous studies have shown that sodium channels cluster together in specific cellular subdomains.

Alterations of Ca signaling and Ca release sites in cultured ventricular myocytes with intact internal Ca storage.

Although cultured adult cardiac myocytes in combination with cell-level genetic modifications have been adopted for the study of protein function, the cellular alterations caused by the culture conditions themselves need to be clarified before we can interpret the effects of genetically altered proteins. We systematically compared the cellular morphology, global Ca signaling, elementary Ca release (sparks), and arrangement of ryanodine receptor (RyR) clusters in short-term (2 days)-cultured adult rat ventricular myocytes with those of freshly isolated myocytes. The transverse (t)-tubules were remarkably decreased (to ∼25%) by culture, and whole-cell capacitance was reduced by ∼35%.

Distinct shear-induced Ca signaling in the left and right atrial myocytes: Role of P2 receptor context.

Atrial myocytes are continuously exposed to shear stress during cardiac cycles. Previous reports have shown that shear stress induces two different types of global Ca signaling in atrial myocytes-longitudinal Ca waves (L-waves) and action potential-involved transverse waves (T-waves), and suggested an underlying role of the autocrine activation of P2 receptors. We explored the correlations between ATP release and Ca wave generation in atrial myocytes and investigated why the cells develop two Ca-wave types during the same shear force.

Ca2+ Signaling Triggered by Shear-Autocrine P2X Receptor Pathway in Rat Atrial Myocytes.

Background/aims: The atrium is exposed to high shear stress during heart failure and valvular diseases. We aimed to understand atrial shear-induced Ca2+ signaling and its underlying mechanisms.

Methods: Pressurized micro-flow was applied to single rat atrial myocytes, and Ca2+ signal, membrane potential, and ATP release were assessed using confocal imaging, patch clamp technique, and luciferin-luciferase assay, respectively.

Role of inositol 1,4,5-trisphosphate receptor type 1 in ATP-induced nuclear Ca signal and hypertrophy in atrial myocytes.

Inositol 1,4,5-trisphosphate receptor type 1 (IPR1) is expressed in atrial muscle, but not in ventricle, and they are abundant in the perinucleus. We investigated the role of IPR1 in the regulations of local Ca signal and cell size in HL-1 atrial myocytes under stimulation by IP-generating chemical messenger, ATP. Assessment of nuclear and cytosolic Ca signal using confocal Ca imaging revealed that IP generation by ATP (1 mM) induced monophasic nuclear Ca increase, followed by cytosolic Ca oscillation.

Regulation of cardiac Ca and ion channels by shear mechanotransduction.

Cardiac contraction is controlled by a Ca signaling sequence that includes L-type Ca current-gated opening of Ca release channels (ryanodine receptors) in the sarcoplasmic reticulum (SR). Local Ca signaling in the atrium differs from that in the ventricle because atrial myocytes lack transverse tubules and have more abundant corbular SR. Myocardium is subjected to a variety of forces with each contraction, such as stretch, shear stress, and afterload, and adapts to those mechanical stresses.

Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII.

Background/aims: Endothelin-1 (ET-1) and the α₁-adrenoceptor agonist phenylephrine (PE) activate cAMP response element binding protein (CREB), a transcription factor implicated in cardiac hypertrophy. The signaling pathway involved in CREB activation by these hypertrophic stimuli is poorly understood. We examined signaling pathways for ET-1- or PE-induced cardiac CREB activation.

Shear stress enhances Ca sparks through Nox2-dependent mitochondrial reactive oxygen species generation in rat ventricular myocytes.

Shear stress enhances diastolic and systolic Ca concentration in ventricular myocytes. Here, using confocal Ca imaging in rat ventricular myocytes, we assessed the effects of shear stress (~16dyn/cm) on the frequency of spontaneous Ca sparks and explored the mechanism underlying shear-mediated Ca spark regulation. The frequency of Ca sparks was immediately increased by shear stress (by ~80%), and increased further (by ~150%) during prolonged exposure (20s).

Cardiac inotropy, lusitropy, and Ca handling with major metabolic substrates in rat heart.

Fatty acid (FA)-dependent oxidation is the predominant process for energy supply in normal heart. Impaired FA metabolism and metabolic insufficiency underlie the failing of the myocardium. So far, FA metabolism in normal cardiac physiology and heart failure remains undetermined.

Health Related Quality of Life in Patients with Side-Effects after Antimuscarinic Treatment for Overactive Bladder.

Objectives: Drug therapy is the mainstay of treatment for overactive bladder (OAB), but antimuscarinic agents possess side-effects. These side-effects decrease the patients' quality of life. We therefore assessed the impact of side-effects on health-related quality of life (HR-QoL) through an analysis of EQ-5D questionnaire.

Enhancement of contraction and L-type Ca(2+) current by murrayafoline-A via protein kinase C in rat ventricular myocytes.

We previously reported that murrayafoline-A (1-methoxy-3-methyl-9H-carbazole, Mu-A) increases the contractility of ventricular myocytes, in part, via enhancing Ca(2+) influx through L-type Ca(2+) channels, and that it increases the Ca(2+) transients by activation of protein kinase C (PKC). In the present study, we further examined the cellular mechanisms for the enhancement of contractility and L-type Ca(2+) current (ICa,L) by Mu-A. Cell shortening and ICa,L were measured in rat ventricular myocytes using a video edge detection method and perforated patch-clamp technique, respectively.

Shear stress activates monovalent cation channel transient receptor potential melastatin subfamily 4 in rat atrial myocytes via type 2 inositol 1,4,5-trisphosphate receptors and Ca(2+) release.

Key Points: During each contraction and haemodynamic disturbance, cardiac myocytes are subjected to fluid shear stress as a result of blood flow and the relative movement of sheets of myocytes. The present study aimed to characterize the shear stress-sensitive membrane current in atrial myocytes using the whole-cell patch clamp technique, combined with pressurized fluid flow, as well as pharmacological and genetic interventions of specific proteins. The data obtained suggest that shear stress indirectly activates the monovalent cation current carried by transient receptor potential melastatin subfamily 4 channels via type 2 inositol 1,4,5-trisphosphate receptor-mediated Ca(2+) release in subsarcolemmal domains of atrial myocytes.

Shear stress induces a longitudinal Ca(2+) wave via autocrine activation of P2Y1 purinergic signalling in rat atrial myocytes.

Atrial myocytes are exposed to shear stress during the cardiac cycle and haemodynamic disturbance. In response, they generate a longitudinally propagating global Ca(2+) wave. Here, we investigated the cellular mechanisms underlying the shear stress-mediated Ca(2+) wave, using two-dimensional confocal Ca(2+) imaging combined with a pressurized microflow system in single rat atrial myocytes.

Sensitization of cardiac Ca²⁺ release sites by protein kinase C signaling: evidence from action of murrayafoline A.

In the present study, we explored the effects of a plant alkaloid compound, 1-methoxy-3-methylcarbazole (murrayafoline A, Mu-A), on focal and global Ca(2+) signaling, and the underlying cellular mechanisms. Rapid two-dimensional confocal Ca(2+) imaging and image analysis were used to measure Ca(2+) signals in rat ventricular myocytes. Application of Mu-A (10-100 μM) significantly enhanced the magnitude and rate of Ca(2+) release on depolarization with no change in Ca(2+) transient decay.

Alterations of contractions and L-type Ca2+ currents by murrayafoline-A in rat ventricular myocytes.

We examined the effects of murrayafoline-A (1-methoxy-3-methylcarbazole, Mu-A), which is isolated from the dried roots of Glycosmis stenocarpa, on cell shortenings and L-type Ca2+ currents (ICa,L) in rat ventricular myocytes. Cell shortenings and ICa,L were measured using the video edge detection method and patch-clamp techniques, respectively. Mu-A transiently increased cell shortenings in a concentration-dependent manner with an EC50 of ~20 μM.